Notch3 is essential for regulation of the renal vascular tone.

The Notch3 receptor participates in the development and maturation of vessels. Mutations of Notch3 in humans are associated with defective regulation of cerebral blood flow. To investigate the role of Notch3 in the regulation of renal hemodynamics, we used mice lacking expression of the Notch3 gene (Notch3-/- mice). Bolus injections of norepinephrine and angiotensin II increased renal vascular resistance and decreased renal blood flow in a dose-dependent manner in wild-type mice. In sharp contrast, renal vascular resistance of Notch3-/- mice varied little after boluses of norepinephrine and angiotensin II. Inversely, bradykinin and prostacyclin relaxed renal vasculature in wild-type mice. Both vasodilators had a negligible effect on renal vascular resistance of Notch3-/- mice. Afferent arterioles freshly isolated from Notch3-/- mice displayed decreased thickness of vascular wall compared with wild -type mice and showed a deficient contractile response to angiotensin II. To examine the physiopathological consequences of the above-described deficiency, hypertension was induced by continuous infusion of angiotensin II. Angiotensin II gradually increased blood pressure in both strains, but this increase was lesser in the Notch3-/- mice. Despite this blunted systemic effect, Notch3-/- mice displayed high mortality rates (65%) attributed to heart failure. In the kidney, the surviving Notch3-/- mice showed focal structural alterations characteristic of nephroangiosclerosis. These data show that Notch3 is necessary for the adaptive response of the renal vasculature to vasoactive systems. A deficiency in the expression of Notch3 could have important physiopathological consequences in the adaptation of the cardiac and renal function to chronic increase of blood pressure.

Tissue transglutaminase contributes to interstitial renal fibrosis by favoring accumulation of fibrillar collagen through TGF-beta activation and cell infiltration.

Renal fibrosis is defined by the exaggerated accumulation of extracellular matrix proteins. Tissue transglutaminase (TG2) modifies the stability of extracellular matrix proteins and renders the extracellular matrix resistant to degradation. In addition, TG2 also activates transforming growth factor-beta (TGF-beta). We investigated the involvement of TG2 in the development of renal fibrosis using mice with a knockout of the TG2 gene (KO). These mice were studied at baseline and 12 days after unilateral ureteral obstruction, which induced a significant increase in interstitial TG2 expression in wild-type mice (P < 0.001). Interstitial fibrosis was evident in both groups, but total and fibrillar collagen was considerably lower in KO mice as compared with wild-type (P < 0.001). Similarly, mRNA and protein expression of collagen I were significantly lower in KO animals (P < 0.05). A statistically significant reduction in renal inflammation and fewer myofibroblasts were observed in KO mice (P < 0.01). Free active TGF-beta was decreased in KO mice (P < 0.05), although total (active + latent) TFG-beta concentration did not differ between groups. These results show that mice deficient in TG2 are protected against the development of fibrotic lesions in obstructive nephropathy. This protection results from reduced macrophage and myofibroblast infiltration, as well as from a decreased rate of collagen I synthesis because of decreased TGF-beta activation. Our results suggest that inhibition of TG2 may provide a new and important therapeutic target against the progression of renal fibrosis.

Nephroangiosclerosis in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy: is NOTCH3 mutation the common culprit?

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a systemic arterial disease characterized by impairment of vascular smooth muscle cell structure and function related to NOTCH3 mutations. Pathological findings include pathognomonic granular osmiophilic material (GOM) deposition with nonspecific hyalinization within the artery wall in a variety of tissues. The main clinical presentation is iterative strokes in young adults despite the lack of cardiovascular risk factors, leading to early dementia. Although arteriosclerosis and GOM have been found in kidneys from patients with CADASIL, kidney disease has been described only once up to now, in association with immunoglobulin A nephropathy. We report the case of a 61-year-old patient with a medical history of CADASIL and recent mild hypertension. His mother also showed neuropsychiatric symptoms and end-stage renal disease of unknown cause. The patient had a chronic kidney disease defined by means of estimated glomerular filtration rate using the 4-variable Modification of Diet in Renal Disease Study equation of 58 mL/min/1.73 m(2) associated with mild proteinuria and intermittent microscopic hematuria. Renal histological analysis showed severe arteriosclerosis and mild interstitial fibrosis. Glomeruli did not show mesangial immunoglobulin A deposition or focal segmental proliferation. Electron microscopic analysis showed typical GOM deposition in the vicinity of altered vascular smooth muscle cells in interlobular and juxtaglomerular arteries. The nephroangiosclerosis-like lesions were unusually severe in contrast to the recent mild hypertension. The presence of GOM strongly suggests that renal lesions were related to the NOTCH3 mutation. Here, we describe the first case of familial occurrence of kidney disease with decreased kidney function in the absence of coexisting nephropathy in patients with CADASIL. We discuss the role of NOTCH3 mutation in the pathogenesis of nephroangiosclerosis through functional impairment of renal microcirculation or primary Notch3-related vascular disease.